Genetic Studies Identify Copy Number Variants Associated with Both ADHD and Autism

Scientists have found a number of de novo and rare inherited copy number variants associated with attention deficit hyperactivity disorder (ADHD). The Canadian researchers identified de novo CNVs in 3 of 173 ADHD patients from whom DNA from both parents was available, and rare inherited CNVs were identified in 7.7% of 248 ADHD patients studied, which were absent in over 2,357 controls.

A number of the CNVs overlapped with previously implicated ADHD loci, but some were associated with new candidate genes including ASTN2, CPLX2, ZBBX, and PTPRNZ. Some of the CNVs were in addition associated with genes that had previously been implicated in other neurodevelopmental conditions such as autism spectrum disorder (ASD).

Reporting their results in Science Translational Medicine, the researchers, led by Stephen W. Scherer, M.D., and Russel Schachar, M.D., at the University of Toronto, says their data reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders. “Overall, we detected rare inherited CNVs at loci previously reported in ADHD or in other neurodevelopmental disorders in 8% of the ADHD sample, suggesting that they may be risk factors for ADHD and/or associated neuropsychiatric phenotypes in the individuals carrying them,” they state.

The researchers’ findings are detailed in a paper titled “Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD.”

The Canadian team studied a well-characterized Canadian cohort to further explore the etiologic role of rare inherited CNVs in ADHD, as well as to determine whether de novo CNV mutations might also contribute to the disorder. The analysis included 248 unrelated ADHD cases including 173 families in which DNA from both parents was genotyped.

A total of 306 rare CNVs were detected in the ADHD patients. To define ADHD candidate loci, the team prioritized de novo CNVs and rare inherited CNVs that overlapped genetic loci previously implicated in ADHD or in other neuropsychiatric disorders. This suggested that the de novo CNV rate in ADHD was about 2%. Among the identified CNVs of note was a deletion in the MACROD2 gene in one ADHD patient. The authors say that although little is known about its function, the MACROD2 gene is expressed in the brain and represented the most significant association in a recently reported genome-wide association analysis of ASD.

Another notable CNV was a 33 kb de novo deletion at 4q31.3 in one male patient with ADHD and anxiety traits who also exhibited seizure-like symptoms. This deletion eliminates two exons of the DCLK2 (double cortin-like kinase 2) gene, and mutations in the paralogous gene DCX have been associated with epilepsy and periodic limb movements, the researchers point out.

In another male patient, a pair of adjacent de novo CNVs at 10q25.1 resulted in duplications that overlapped SORCS3 and SORCS1, which are paralogs encoding sortilin-related VPS10 domain-containing receptor proteins, which are involved in intracellular sorting of surface membrane proteins and are highly expressed in the developing and mature central nervous system. This patient was found to have later been diagnosed with bipolar disorder. “Indeed, variants at SORCS2 (a paralog of SORCS3 and SORCS1 mapping to 4p16.1) have been shown by GWA studies to be potential risk factors for both ADHD and bipolar disorder,” the authors note.

Among rare inherited CNVs that overlapped loci previously reported in genetic studies of ADHD were large inherited duplications at 16p11.2 and 15q13 (found in separate ADHD probands) that support previous reports of ADHD being a frequent phenotypic component in patients with microdeletions and duplications at the two loci.

Other genes of interest implicated by overlap with rare duplications included the dopamine receptor subtype D5 gene (DRD5), and PTPRN2, which has been associated with ADHD traits and with behavioral and learning disturbances in mice with deletion of the PTPRN2 homolog.

There was an overlap of rare CNVs in the ADHD cohort, with those, including CNTN5, GABRG1 and GCNT2, and STK32B, which have previously been implicated in other neuropsychiatric disorders, in particular ASD. This finding led the researchers to look more closely at genes that might be implicated in both conditions. To this end they expanded the case dataset to include 349 newly characterized ASD patients.

The resulting analyses suggested that rare CNVs that overlapped ASTN2 and TRIM32 were present in about 1% of ADHD and ASD patients, but in none of the controls. Three of the four ASD patients with CNVs at this locus also met criteria for ADHD, and the fourth ASD patient was only just below the ADHD diagnosis threshold. “Although exceptionally rare CNVs at this locus have been reported in earlier CNV studies of ASD, bipolar disorder, intellectual disability, and schizophrenia, this is the first report of CNVs at this locus in ADHD,” the authors state.

“Ultimately then, we believe our new results should serve as a conservative starting point for much larger studies exploring the role of de novo and rare CNVs in ADHD, ADHD-related disorders, and other associated clinical co-morbidities.”